Type 1 diabetes is a syndrome defined by high blood glucose levels caused by reduction in number of insulin producing cells, thus a cure for diabetes should entail replacement of -cells. There is a genetic predisposition for autoimmune susceptibility regarding macrophage phenotype in NOD mice and human T1D-patients, which contributes to persistence of inflammation, and -cell destruction. Here, we provide evidence that macrophages are important elements of pancreatic regeneration in general, and -cell generation in particular. Furthermore, we demonstrate that macrophages isolated from the NOD strain have an inherent inability to induce -cell generation. In this proposal, we will test the central hypothesis that Type1 diabetes is the combined effect of autoimmunity and the inability of macrophages to generate a cellular phenotype important for -cell regeneration. The experimental models described in this proposal will allow us to further study the macrophage-dependent -cell proliferation in mice (specific aims 1), to evaluate the ability of human-derived macrophages to induce - cell replication (specific aims 2), and to identify putative factors released by macrophages that are necessary for human -cell generation (specific aims 3). Immune therapy significantly reduces the autoimmune-associated -cell proliferation. Thus, additional therapeutic approaches that would stimulate -cell regeneration in the absence of autoimmune destruction may be needed for recovery of -cell mass. As a potential cell therapeutic approach, macrophages generated from patient's monocytes could be reprogrammed to promote -cell regeneration. This work is a high priority area as it is directly applicable to our full understanding and potential treatment of T1D.